Pyrido (2,3-B) pyrazine derivatives

ABSTRACT

A compound of the formula: ##STR1## wherein R 1  is pyridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl, 
     R 2  is aminophenyl, [protected amino]phenyl, [[[halophenyl](lower)alkenoyl]amino]phenyl, [[pyridyl(lower)alkenoyl]amino]phenyl, [[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protected aminopyridyl](lower)alkenoyl]amino]phenyl, [thiazolylcarbonylamino]phenyl which may have pyridyl, naphthyl having lower alkoxy and halogen, [dihalophenyl](lower)alkenyl, [N-oxidopyridyl](lower)alkenyl, [aminopyridyl](lower)alkenyl, [protected aminopyridyl](lower)alkenyl, [carboxypyridyl](lower)alkenyl, [protected carboxypyridyl](lower)alkenyl, [[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl, [[carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [[protected carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [pyridyl(lower)alkenyl]pyridyl, lower alkylbenzothiazolyl or [halopyridylcarbonyl]amino, 
     with proviso that when R 2  is [[4-pyridyl(lower)alkenoyl]amino]phenyl, aminophenyl, [lower alkanoylamino]phenyl or [dihalophenyl](lower)alkenyl, then 
     R 1  is N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl, 
     and a pharmaceutically acceptable salt thereof, which is useful as a medicament.

This is a 371 application of PCT/JP96/03666 filed on Dec. 13, 1996.

TECHNICAL FIELD

This invention relates to new heterobicyclic derivatives.

One object of this invention is to provide the new and usefulpyridopyrazine derivatives and pharmaceutically acceptable salts thereofwhich possess a strong phosphodiesterase IV (PDE IV)-inhibitory activityand a strong inhibitory activity on the production of tumor necrosisfactor (TNF).

Another object of this invention is to provide processes for preparationof the pyridopyrazine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceuticalcomposition comprising said pyridopyrazine derivatives or apharmaceutically acceptable salt thereof.

Still further object of this invention is to provide a use of saidpyridopyrazine derivatives or a pharmaceutically acceptable salt thereofas a medicament for prophylactic and therapeutic treatment of PDE-IV andTNF mediated diseases such as chronic inflammatory diseases, specificautoimmune diseases, sepsis-induced organ injury, and the like in humanbeing and animals.

DISCLOSURE OF INVENTION

The object pyridopyrazine derivatives of the present invention are noveland can be represented by the following general formula (I): ##STR2##wherein R¹ is pyridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl orimidazolyl(lower)alkyl,

R² is aminophenyl, [protected amino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl,[thiazolylcarbonylamino]phenyl which may have pyridyl, naphthyl havinglower alkoxy and halogen, [dihalophenyl](lower)alkenyl,[N-oxidopyridyl](lower)alkenyl, [aminopyridyl](lower)alkenyl, [protectedaminopyridyl](lower)alkenyl, [carboxypyridyl](lower)alkenyl, [protectedcarboxypyridyl](lower)alkenyl,[[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl,[[carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [[protectedcarboxy(lower)alkenyl]pyridyl](lower)alkenyl,[pyridyl(lower)alkenyl]pyridyl, lower alkylbenzothiazolyl or[halopyridylcarbonyl]amino,

with proviso that when R² is [[4-pyridyl(lower)alkenoyl]amino]phenyl,aminophenyl, [lower alkanoylamino]phenyl or[dihalophenyl](lower)alkenyl, then

R¹ is N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl.

The object compound (I) of the present invention can be prepared by thefollowing processes. ##STR3## wherein

R¹ and R² are each as defined above,

R_(a) ² is [aminopyridyl](lower)alkenyl,

R_(b) ² is [acylaminopyridyl](lower)alkenyl,

R_(c) ² is [lower alkanoylamino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl,[thiazolylcarbonylamino]phenyl which may have pyridyl or[acylaminopyridyl](lower)alkenyl,

R_(d) ² is aminophenyl or [aminopyridyl](lower)alkenyl,

R_(e) ² is aminophenyl,

R_(f) ² is [lower alkanoylamino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl or[thiazolylcarbonylamino]phenyl which may have pyridyl,

R³ is lower alkanoyl, [halophenyl](lower)alkenoyl,pyridyl(lower)alkenoyl, [N-oxidopyridyl](lower)alkenoyl, [protectedaminopyridyl](lower)alkenoyl or thiazoylcarbonyl which may have pyridyl,

R⁴ is N-protective group,

Y is halogen,

Y⁻ is halide, and

A is lower alkylene.

The starting compound (II) of the present invention can be prepared bythe following processes. ##STR4## wherein

R², R_(e) ², R_(f) ² and R³ are each as defined above,

R⁵ is lower alkyl,

R⁶ is protected aminophenyl,

R⁷ is aminophenyl,

R⁸ is dihalophenyl, N-oxidopyridyl, aminopyridyl, protectedaminopyridyl, carboxypyridyl, protected carboxypyridyl,[pyridyl(lower)alkenyl]pyridyl, [carboxy(lower)alkenyl]pyridyl or[protected carboxy(lower)alkenyl]pyridyl,

R⁹ is halo(lower)alkyl,

X¹, X², X³, X⁴ and X⁵ are each a leaving group, and

Q is lower alkenylene.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salts and may include a salt with a base oran acid addition salt such as a salt with an inorganic base, forexample, an alkali metal salt (e.g., sodium salt, potassium salt, etc.),an alkaline earth metal salt (e.g.., calcium salt, magnesium salt,etc.), an ammonium salt; a salt with an organic base, for example, anorganic amine salt (e.g., triethylamine salt, pyridine salt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid additionsalt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); anorganic carboxylic or sulfonic acid addition salt (e.g., formate,acetate, trifluoroacetate, maleate, tartrate, fumarate,methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt witha basic or acidic amino acid (e.g., arginine, aspartic acid, glutamicacid, etc.).

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

The term "lower" is used to intend a group having 1 to 6, preferably 1to 4, carbon atom(s), unless otherwise provided.

The term "higher" is used to intend a group having 7 to 20 carbon atoms,unless otherwise provided.

Suitable "lower alkyl" and "lower alkyl moiety" in the terms"pyridyl(lower)alkyl", "N-oxidopyridyl(lower)alkyl","imidazolyl(lower)alkyl", "lower alkylbenzothiazolyl" and"halo(lower)alkyl" may include straight or branched one having 1 to 6carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and thelike, and in which more preferable example may be C₁ -C₄ alkyl, and themost preferable one may be methyl.

Suitable "lower alkenyl" and "lower alkenyl moiety" in the terms"[dihalophenyl](lower)alkenyl", "[N-oxidopyridyl](lower)alkenyl","[aminopyridyl](lower) alkenyl", "[protectedaminopyridyl](lower)alkenyl", "[carboxypyridyl](lower)alkenyl","[protected carboxypyridyl](lower)alkenyl",[[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl","[[carboxy(lower)alkenyl]pyridyl](lower)alkenyl", [[protectedcarboxy(lower)alkenyl]pyridyl](lower)alkenyl" and"[pyridyl(lower)alkenyl]pyridyl" may include vinyl, 1- (or 2-)propenyl,1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1-(or2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferableexample may be C₂ -C₄ alkenyl, and the most preferable one may be vinyl.

Suitable "lower alkynyl" may include ethynyl, 1-propynyl, propargyl,1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or2 or 3 or 4 or 5-hexynyl, and the like.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy,hexyloxy and the like.

Suitable "lower alkylene" may include straight or branched one such asmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, methylmethylene, ethylethylene, propylene, and the like,in which more preferable example may be C₁ -C₄ alkylene and the mostpreferable one may be methylene.

Suitable "lower alkenylene" may include straight or branched one having2 to 6 carbon atom(s) such as vinylene, propenylene, 1-(or2-)butenylene, 1-(or 2- or 3-)pentenylene, 1-(or 2- or 3-)hexenylene,methylvinylene, ethylvinylene, 1-(or 2- or 3-)methylpropenylene, 1-(or2- or 3-)ethylpropenylene, 1-(or 2- or 3- or 4-)methyl-1-(or2-)butenylene, and the like.

Suitable "cyclo(lower)alkyl" may include cyclopentyl, cyclohexyl and thelike.

Suitable "cyclo(lower)alkenyl" may include cyclohexenyl, cyclohexadienyland the like.

Suitable "aryl" may include phenyl, naphthyl and the like.

Suitable "halogen" and "halogen moiety" in the terms "halo(lower)alkyl",[[[halophenyl](lower)alkenoyl]amino]phenyl","[dihalophenyl](lower)alkenyl" and "[halopyridylcarbonyl]amino" mayinclude fluorine, bromine, chlorine and iodine.

Suitable "leaving group" may include acid residue, lower alkoxy asexemplified above, and the like.

Suitable "acid residue" may include halogen as exemplified above,acyloxy and the like.

Suitable "halide" may include fluoride, bromide, chloride and the like.

Suitable "protected carboxy" and "protected carboxy moiety" in the terms"[protected carboxypyridyl](lower)alkenyl and [[protectedcarboxy(lower)alkenyl]pyridyl](lower)alkenyl" may include esterifiedcarboxy and the like. And suitable example of said ester may be the onessuch as lower alkyl ester (e.g., methyl ester, ethyl ester, propylester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester,pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester(e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g.ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester(e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester,1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); loweralkylthio(lower)alkyl ester (e.g., methylthiomethyl ester,ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl ester,etc.); mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethylester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkylester (e.g., acetoxymethyl ester, propionyloxymethyl ester,butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester,2-propionyloxyethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkylester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethylester, propoxycarbonyloxymethyl ester, 1-(or2-)[methoxycarbonyloxy]ethyl ester, 1-(or 2-)[ethoxycarbonyloxy]ethylester, 1-(or 2-)[propoxycarbonyloxy]ethyl ester, 1-(or2-)[isopropoxycarbonyloxy]ethyl ester, etc.); loweralkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethylester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g.,methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester,propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester,1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.);phthalidylidene(lower)alkyl ester; (5-loweralkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; mono(or di ortri)alkyl(lower)alkyl ester, for example, mono(or di ortri)phenyl(lower)alkyl ester which may have one or more suitablesubstituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzylester, phenethyl ester, trityl ester, benzhydryl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may haveone or more suitable substituent(s) such as substituted or unsubstitutedphenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester,xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester,4-methoxyphenyl ester, etc.); tri(lower)alkylsilyl ester; loweralkylthioester (e.g. methylthioester, ethylthioester, etc.) and thelike, in which more preferable example may be C₁ -C₄ alkoxycarbonyl andthe most preferable one may be methoxycarbonyl.

Suitable "hydroxy protective group" in the term "protected hydroxy" mayinclude acyl, mono(or di or tri)phenyl(lower)alkyl which may have one ormore suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl,etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g.,trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyland the like.

Suitable "N-protective group" may include acyl or a conventionalprotecting group such as mono (or di or tri)aryl(lower)alkyl, forexample, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, trityl,etc.) or the like.

Suitable "protected amino" and "protected amino moiety" in the terms"[protected amino]phenyl", "[[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl" and "[protectedaminopyridyl](lower)alkenyl]" may include acylamino or an amino groupsubstituted by a conventional protecting group such as mono (or di ortri)aryl(lower)alkyl, for example, mono(or di or tri)phenyl(lower)alkyl(e.g., benzyl, trityl, etc.) or the like.

Suitable "acyl" and "acyl moiety" in the terms "acylamino" and "acyloxy"may include carbamoyl, thiocarbamoyl, aliphatic acyl group and acylgroup containing an aromatic ring, which is referred to as aromaticacyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows:

Carbamoyl; Thiocarbamoyl;

Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl,pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl,icosanoyl, etc.);

lower or higher alkenoyl (e.g., acryloyl, 2-(or 3-)butenoyl, 2-(or 3- or4-)pentenoyl, 2-(or 3- or 4- or 5-)hexenoyl, etc.);

lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl,heptyloxycarbonyl, etc.);

lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,etc.);

lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl,etc.);

lower alkadienoyl (e.g., heptadienoyl, hexadienoyl, etc.);

cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, etc.);

cyclo(lower)alkylidene(lower)alkanoyl (e.g., cycloheptylideneacetyl,cycloheptylidenepropanoyl, cyclohexylideneacetyl,cyclohexylidenepropanoyl, etc.);

cyclo(lower)alkyloxycarbonyl (e.g., cyclopentyloxycarbonyl,cyclohexyloxycarbonyl, etc.);

lower alkylglyoxyloyl (e.g., methylglyoxyloyl, ethylglyoxyloyl,propylglyoxyloyl, etc.);

lower alkoxyglyoxyloyl (e.g., methoxyglyoxyloyl, ethoxyglyoxyloyl,propoxyglyoxyloyl, etc.);

or the like;

Aromatic acyl such as

aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);

ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl,phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl,naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];

ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl,phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl,etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl,naphthylbutenoyl, etc.), etc.];

ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g.,benzyloxycarbonyl, etc.), etc.];

aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);

aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);

arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);

arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.);ar(lower)alkylsulfonyl [e.g., phenyl(lower)alkylsulfonyl (e.g.,benzylsulfonyl, phenylethylsulfonyl, etc.), naphthyl(lower)alkylsulfonyl(e.g., naphthylmethylsulfonyl, naphthylethylsulfonyl, etc.), etc.]; orthe like;

Heterocyclic acyl such as

heterocycliccarbonyl;

heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl,heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl,heterocyclichexanoyl, etc.);

heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl,heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl,etc.); heterocyclicglyoxyloyl;

heterocyclicoxycarbonyl; or the like;

in which suitable "heterocyclic moiety" in the terms"heterocycliccarbonyl", "heterocyclic(lower)alkanoyl",heterocyclic(lower)alkenoyl", heterocyclicoxycarbonyl and"heterocyclicglyoxyloyl" as mentioned above means, in more detail,saturated or unsaturated, monocyclic or polycyclic heterocyclic groupcontaining at least one hetero-atom such as an oxygen, sulfur, nitrogenatom and the like.

And, especially preferable heterocyclic group may be heterocyclic groupsuch as

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,2H-tetrazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl,benzimidazolyl, quinolyl, tetrahydroquinolyl (e.g.,1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, indazolyl,benzotriazolyl, benzopyrimidinyl (e.g., benzo[b]pyrimidinyl, etc.),etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s), for example, benzodioxolyl (e.g. methylenedioxyphenyl, etc.),benzofuryl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl (e.g., benzo[b]thienyl, etc.),benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.

The acyl moiety as stated above may have one to ten, same or different,suitable substituent(s) such as lower alkyl as exemplified above, loweralkoxy as exemplified above, lower alkylthio wherein lower alkyl moietyis as exemplified above, cyclo(lower)alkyl as exemplified above,cyclo(lower)alkenyl as exemplified above, cyclo(lower)alkyloxy whereincyclo(lower)alkyl moiety is as exemplified above, halogen as exemplifiedabove, amino, protected amino as exemplified above, hydroxy, protectedhydroxy as exemplified above, cyano, nitro, carboxy, protected carboxyas exemplified above, sulfo, sulfamoyl, imino, oxo, amino(lower)alkylwherein lower alkyl moiety is as exemplified above, carbamoyloxy,mono(or di or tri)halo(lower)alkyl wherein halogen moiety and loweralkyl moiety are each as exemplified above, hydroxy(lower)alkyl whereinlower alkyl moiety is as exemplified above, heterocyclic group asexemplified above, heterocyclicoxy wherein heterocyclic moiety is asexemplified above, heterocyclicamino which may have nitro whereinheterocyclic moiety is as exemplified above, aryl which may havesuitable substituent(s) wherein aryl moiety is as exemplified above,arylsulfonyl wherein aryl moiety is as exemplified above, ar(lower)alkylwherein aryl moiety and lower alkyl moiety are each as exemplifiedabove, protected carboxy(lower)alkenyl wherein protected carboxy moietyand lower alkenyl moiety are each as exemplified above, acyl asexemplified above, acylamino wherein acyl moiety is as exemplifiedabove, or the like.

Preferable acyl thus defined may be aliphtic acyl such as lower alkanoyl(e.g. acetyl, etc.) and the most preferable one may be acetyl.

Suitable "lower alkanoyl moiety" in the term "[loweralkanoylamino]phenyl" can be referred to the ones as mentioned above.

Suitable "lower alkenoyl moiety" in the terms"[[[halophenyl](lower)alkenoyl]amino]phenyl","[[pyridyl(lower)alkenoyl]amino]phenyl",[[[(N-oxidopyridyl](lower)alkenoyl]amino]phenyl" and "[[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl" can be referred to the onesas mentioned above.

The processes for preparing the object and the starting compounds areexplained in detail in the following.

Process (1)

The compound (I) or a salt thereof can be prepared by reacting thecompound (II) or a salt thereof with the compound (III) or a saltthereof.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, diethyl ether or any other solvent which does not adverselyaffect the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under warming to heating.

Process (2)

The compound (Ib) or a salt thereof can be prepared by subjecting thecompound (Ia) or its reactive derivative at the amino group or a saltthereof to acylation reaction.

Suitable acylating agent to be used in the present acylation reactionmay include the compound of the formula:

    R.sup.11 --OH                                              (XXV)

(wherein R¹¹ is acyl)

or its reactive derivative or a salt thereof.

Suitable reactive derivative at the amino group of the compound (Ia) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (Ia) with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound (Ia) with a silyl compound such asN,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like;a derivative formed by the reaction of the compound (Ia) with phosphorustrichloride or phosgene, and the like.

Suitable reactive derivative of the compound (XXV) may include an acidhalide, an acid anhydride, an activated ester, isocyanate, and the like.The suitable example may be an acid chloride; acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid (e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfuric acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethylester, dimethyliminomethyl [(CH₃)₂ ⁺ N═CH--] ester, vinyl ester,propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with aN-hydroxy compound (e.g., N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole,N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.);substituted or unsubstituted aryl isocyanate; substituted orunsubstituted aryl isothiocyanate, and the like. These reactivederivatives can optionally be selected from them accordingly to the kindof the compound (XXV) to be used.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvents which donot adversely influence the reaction. These conventional solvents mayalso be used in a mixture with water.

When the compound (XXV) is used in free acid form or its salt form inthe reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonyl-bis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate;phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride;thionyl chloride; oxalyl chloride; triphenylphosphite;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an organic orinorganic base such as an alkali metal bicarbonate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine,N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to heating.

Process (3)

The compound (Id) or a salt thereof can be prepared by subjecting thecompound (Ic) or a salt thereof to deacylation reaction.

Suitable method of this deacylation reaction may include conventionalone such as hydrolysis, reduction and the like.

(i) For Hydrolysis:

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal[e.g., magnesium, calcium, etc.], the hydroxide or carbonate orhydrogencarbonate thereof, trialkylamine [e.g., trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, or thelike.

Suitable acid may include an organic acid [e.g., formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.],and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].

The elimination using Lewis acid such as trihaloacetic acid [e.g.,trichloroacetic acid, trifluoroacetic acid, etc.], or the like ispreferably carried out in the presence of cation trapping agents [e.g.,anisole, phenol, etc.].

The reaction is usually carried out in a conventional solvent such aswater, alcohol (e.g., methanol, ethanol, isopropyl, alcohol, etc.),tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvents which do not adversely affect the reaction,or the mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

(ii) For Reduction:

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing reagent to be used in chemical reduction are hydrides(e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride,sodium borohydride, sodium cyanoborohydride, etc.), or a combination ofa metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g.,chromium chloride, chromium acetate, etc.) and an organic acid or aninorganic acid (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g., platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalysts (e.g., spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.), nickel catalysts(e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobaltcatalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts(e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.

The reduction is usually carried out in a conventional solvent such aswater, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.),tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvents which do not adversely affect the reaction,or the mixture thereof.

Additionally, in case that the above-mentioned acids to be used inchemical reduction are in liquid, they can also be used as a solvent.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

Process (4)

The compound (If) or a salt thereof can be prepared by reacting thecompound (Ie) or its reactive derivative at the amino group, or a saltthereof with the compound (IV) or its reactive drivative at the carboxygroup, or a salt thereof.

This reaction can be carried out in a similar manner to that of theaforementioned Process (2), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of the Process (2).

Process (5)-1

The compound (VII) or a salt thereof can be prepared by reacting thecompound (Va) or a salt thereof with the compound (VI) or a saltthereof.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, dioxane, diethyl ether or any other solvents which do notadversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

The reaction is usually carried out in the presence of an acid includingLewis acid.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g.zinc chloride, zinc bromide, etc.), etc.] and the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal (e.g., sodium, potassium, etc.),an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,etc.), an alkali metal hydrogencarbonate (e.g., sodiumhydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metalcarbonate (e.g., sodium carbonate, potassium carbonate, etc.),tri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), alkali metal hydride (e.g., sodiumhydride, etc.), alkali metal (lower)alkoxide (e.g., sodium methoxide,sodium ethoxide, etc.), pyridine, lutidine, picoline,dimethylaminopyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

When the base, the acid and/or the starting compound are in liquid, theycan be used also as a solvent.

Process (5)-2

The compound (Ig) or a salt thereof can be prepared by subjecting thecompound (VII) or a salt thereof to elimination reaction of N-protectivegroup.

This reaction can be carried out in a similar manner to that of theaforementioned Process (3), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of the Process (3).

Process (A)

The compound (X) or a salt thereof can be prepared by reacting thecompound (VIII) or a salt thereof with the compound (IX) or a saltthereof.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, toluene, methylene chloride, ethylene dichloride,chloroform, diethyl ether or any other solvent which does not adverselyaffect the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under warming to heating.

When the starting compound is in liquid, it can be also used as asolvent.

Process (B)

The compound (II) or a salt thereof can be prepared by subjecting thecompound (X) or a salt thereof to reduction reaction.

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing reagent to be used in chemical reduction are hydrides(e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride,sodium borohydride, sodium cyanoborohydride, etc.) or a combination of ametal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromiumchloride, chromium acetate, etc.) and an organic acid or an inorganicacid (e.g., formic acid, acetic acid, propionic acid, trifluoroaceticacid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid,etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g., platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalysts (e.g., spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.), nickel catalysts(e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobaltcatalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts(e.g., reduced iron, Raney iron, etc.), copper catalysts (e.g., reducedcopper, Raney copper, Ullman copper, etc.) and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, alcohol (e.g.,methanol, ethanol, propanol, etc.), tetrahydrofuran, dioxane,N,N-dimethylformamide, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process (C)

The compound (XI) or a salt thereof can be prepared by reacting thecompound (II) or a salt thereof with the compound (XXIV) or a saltthereof.

This reaction can be carried out in a similar manner to that of theaforementioned Process (1), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of the Process (1).

Process (D)

The compound (IX) or a salt thereof can be prepared by subjecting thecompound (XII) or a salt thereof to reduction reaction.

This reaction can be carried out in a similar manner to that of theaforementioned Process (B), and therefore the reagents to be used andthe reaction conditions (e.g., solvent, reaction temperature, etc.) canbe referred to those of the Process (B).

Process (E)

The compound (IIa) or a salt thereof can be prepared by subjecting thecompound (XIII) or a salt thereof to elimination reaction of the aminoprotective group.

The reaction can be carried out in the manner disclosed in Preparation 5or 6 or similar manners thereto.

Process (F)

The compound (Xb) or a salt thereof can be prepared by reacting thecompound (Xa) or its reactive derivative at the amino group, or a saltthereof with the compound (IV) or its reactive derivative at the carboxygroup, or a salt thereof.

The reaction can be carried out in the manner disclosed in Preparation16 or similar manners thereto.

Process (G)

The compound (XIIa) or a salt thereof can be prepared by reacting thecompound (XIV) with the compound (XV) or a salt thereof.

The reaction can be carried out in the manner disclosed in Preparation 1or similar manners thereto.

Process (H)

The compound (IX) or a salt thereof can be prepared by reacting thecompound (XVII) or a salt thereof with the compound (XVIII) or a saltthereof.

The reaction can be carried out in the manner disclosed in Preparation3, or similar manners thereto.

Process (I)

The compound (Xc) or a salt thereof can be prepared by reacting thecompound (XIX) or a salt thereof with the compound (XX).

The reaction can be carried out in the manner disclosed in Preparation10 or similar manners thereto.

Process (J)

The compound (V) or a salt thereof can be prepared by subjecting thecompound (XI) or a salt thereof to halogenation reaction.

The reaction can be carried out in the manner disclosed in Preparation25 or similar manners thereto.

Process (K)

The compound (XXIIa) or a salt thereof can be prepared by reacting thecompound (XIV) with the compound (XXI) or a salt thereof.

The reaction can be carried out in the manner disclosed in Preparation 2or similar manners thereto.

Process (L)

The compound (XIIb) or a salt thereof can be prepared by reacting thecompound (XXII) or a salt thereof with the compound (XXIII) or a saltthereof.

The reaction can be carried out in the manner disclosed in Preparation12 or similar manners thereto.

Suitable salts of the object and the starting compounds in Processes(1)pb(5) and (A)pb(L) can be referred to the ones as exemplified for thecompound (I).

The new pyridopyrazine derivatives (I) and pharmaceutically acceptablesalts thereof hardly possess a strong inhibitory activity againstphosphodiesterase III (PDE III), but possess a strong inhibitoryactivity against phosphodiesterase IV (PDE IV) and a strong inhibitoryactivity on the tumor necrosis factor (TNF).

That is, the pyridopyrazine derivatives (I) and pharmaceuticallyacceptable salts thereof are selective inhibitors of phosphodiesteraseIV (PDE IV) and inhibitors on the production of tumor necrosis factor(TNF).

Accordingly, the new pyridopyrazine derivatives (I) and apharmaceutically acceptable salt thereof can be used for prophylacticand therapeutic treatment of PDE-IV and TNF mediated diseases such aschronic inflammatory diseases (e.g., rheumatoid arthritis,osteoarthritis, emphysema, chronic bronchiolitis, etc.), osteoporosis,rejection by transplantation, asthma, eosinophilia, cystic fibrosis,hepatitis, pancreatitis, nephritis, endotoxin shock, specific autoimmunediseases (e.g., ankylosing spondylitis, autoimmune hematologicaldisorders (e.g., hemolyticodo anaemia, aplastic anaemia, pure red cellanaemia, idiopathic thrombocytopenia, etc.), systemic lupuserythematosus, polychondritis, scleroderma, Wegener granulamotosis,dermatomyositis, chronic active hepatitis, myasthenia gravis, atopicdermatitis, psoriasis, idiopathic sprue, autoimmune inflammatory boweldisease (e.g., ulcerative colitis, Crohn's disease, etc.), endocrineophthalmopathy, Grave's disease, sarcoidosis, multiple sclerosis,primary biliary cirrhosis, diabetes [e.g. juvenile diabetes (diabetesmellitus type I), etc.], Reiter's syndrome, non infection uveitis,autoimmune keratitis (e.g., keratoconjunctivitis sicca, vernalkeratoconjunctivitis, etc.), interstitial lung fibrosis, psoriaticarthritis, etc.], cancer cachexia, AIDS cachexia, thrombosis, and thelike.

In order to show the utilities of the pyridopyrazine derivatives (I) anda pharmaceutically acceptable salt thereof of the present invention,pharmacological test data of the representative compound of thepyridopyrazine derivatives (I) are illustrated in the following.

(a) Inhibition of U937 phosphodiesterase IV (PDE IV)

1. Test Method:

Harvested U937 was freezed in -80pbC. and throwed to destroy the cellbody. The pellet of destroyed cell was washed by Phosphate-bufferedsaline (PBS).

The washed cell pellet was homogenized with Dounce homogenizer (20strokes) in homogenizing buffer (0.5% deoxycholate [DOC], 5 mM2-mercaptoethanol, 1 μM leupeptin, 100 μM PMSF, 20 μMp-tosyl-L-lysine-chloromethyl ketone [TLCK] in PBS). The homogenate wascentrifuged at 100,000 g×90 minutes (4pbC.) and the supernatantcontaining PDE IV activity was dialyzed against dialysis buffer, whichwas the same component as homogenizing buffer without DOC. The dialyzedsupernatant of homogenate was stored in freezer (-80pbC.) as PDE IVenzyme preparation.

Enzyme preparation was diluted in assay buffer (10 mM Tris-HCl, 5 mMMgCl, 1 mM 2-Mercaptoethanol [pH 8.0]). In advance the rate of dilutionwas choosen every new lot of homogenizing preparation. For blank, a partof the enzyme preparation was boiled for 10 minutes.

Test compounds were dissolved in dimethylsulfoxide (DMSO) at aconcentration of 4×10(-2)[M] (final conc. 1×10(-5)M), then serialdilutions were made in DMSO to achieve desired concentrations. Thediluted compounds of each concentration were further diluted 1:500 inassay buffer (0.2% DMSO). Final DMSO concentration in assay tube was0.025%.

In duplicate, the followings were added to a glass tube, in order, at0pbC. (all concentrations are given as final concentrations in assaytube).

50 μl compound or assay buffer for control or blank

50 μl 8×10(-5)[M] CI-930 (final 10 μM): (CI-930 is PDE III inhibitor)

200 μl enzyme preparation or boiled enzyme preparation for blank.

The reaction tube was preincubated in a water bath (30pbC.) for 5minutes, then 100 μl [³ H]-cAMP (37.0 MBq/ml [³ H]-cAMP: 4 μM coldcAMP=1:800) was added thereto. After 15 minutes, 2.5 units/ml alkalinephosphatase was added to the reaction mixture and the reaction wascontinued for 15 minutes. Dowex 1×8 gel was added to the reactionmixture and was vortexed well. The mixture was centrifuged at 1000 rpm×5minutes, and then 500 μl of the supernatant was added to 10 mlscintillation fluid in appropriate vial, vortexed, and counted for [³H].

The inhibitory activity was calculated according to the followingequation: ##EQU1##

2. Test Compound:

(a)4-[3-[3-[(E)-3-(6-acetanido-3-pyridyl)acryloylanino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.

3. Test Result:

    ______________________________________                                        Test compound  IC.sub.50 (M)                                                  ______________________________________                                          (a) 1.6 × 10.sup.-8                                                   ______________________________________                                    

(b) Inhibition on TNF-α production in human mononuclear cells.

1. Test Method:

Blood was drawn from healthy volunteers with heparin. The mononuclearcell (MNC) fraction was obtained by gradient centrifugation (1800 rpm,15 minutes), diluted with the same volume of RPMI-1640 culture medium,over Ficoll-Paque (Pharmacia LKB Biotechnology). MNC were washed twicewith RPMI-1640. Then, MNC were resuspended in RPMI-1640 culture mediumsupplemented with 2 mM L-glutamine and 1% fetal bovine serum. MNC wereincubated at 37pbC. for 16 hours in 96-well micro culture plate at aconcentration of 3×10⁵ cells/well with or without 1 μg/mllipopolysaccharide (LPS) (from E. coli) and various amounts of testcompound. At the end of incubation, the supernatant was obtained and itsTNF-α active was measured by enzyme-linked immunosorbent assay (ELISA).ELISA was performed with TNF-α ELISA kit (Otsuka Pharmaceutical Co.,Ltd.).

2. Test Compound:

(a)4-[3-[3-[(E)-3-(6-acetamido-3-pyridyl)acryloylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.

3. Test Result:

    ______________________________________                                        Test compound  IC.sub.50 (M)                                                  ______________________________________                                          (a) 2.4 × 10.sup.-8                                                   ______________________________________                                    

For therapeutic administration, the object compounds (I) of the presentinvention and pharmaceutically acceptable salts thereof are used in aform of the conventional pharmaceutical preparation in admixture with aconventional pharmaceutically acceptable carrier such as an organic orinorganic solid or liquid excipient which is suitable for oral,parenteral or external administration. The pharmaceutical preparationmay be compounded in a solid form such as granule, capsule, tablet,dragee or suppository, or in a liquid form such as solution, suspensionor emulsion for injection, ingestion, eye drops, etc. If needed, theremay be included in the above preparation auxiliary substance such asstabilizing agent, wetting or emulsifying agent, buffer or any othercommonly used additives.

The effective ingredient may usually be administered with a unit dose of0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4times a day. However, the above dosage may be increased or decreasedaccording to age, weight and conditions of the patient or theadministering method.

Preferred embodiments of the object compound (I) are as follows.

R¹ is pyridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl orimidazolyl(lower)alkyl,

R² is aminophenyl, [lower alkanoylamino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl,[[[acylaminopyridyl](lower)alkenoyl]amino]phenyl (more preferably[[[[lower alkanoylamino]pyridyl](lower)alkenoyl]amino]phenyl),[[pyridylthiazolyl]carbonylamino]phenyl, naphthyl having lower alkoxyand halogen, [dihalophenyl](lower)alkenyl,[N-oxidopyridyl](lower)alkenyl, [aminopyridyl](lower)alkenyl,[[acylamino]pyridyl](lower)alkenyl(more preferably [[loweralkanoylamino]pyridyl](lower)alkenyl or [[mono(or di ortri)halo(lower)alkanoylamino]pyridyl](lower)alkenyl; most preferably[[lower alkanoylamino]pyridyl](lower)alkenyl or[[trihalo(lower)alkanoylamino]pyridyl](lower)alkenyl),[carboxypyridyl](lower)alkenyl, [esterifiedcarboxypyridyl](lower)alkenyl (more preferably [loweralkoxycarbonylpyridyl](lower)alkenyl),[[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl,[[carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [[esterifiedcarboxy(lower)alkenyl]pyridyl](lower)alkenyl (more preferably [[loweralkoxycarbonyl(lower)alkenyl]pyridyl](lower)alkenyl,[pyridyl(lower)alkenyl]pyridyl, lower alkylbenzothiazolyl orhalopyridylcarbonylamino,

with proviso that when R² is [[4-pyridyl(lower)alkenoyl]amino]phenyl,aminophenyl, [lower alkanoylamino]phenyl or[dihalophenyl](lower)alkenyl, then

R¹ is N-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

PREPARATION 1

A mixture of 3-nitrostyrene (7.0 g), 2-acetamido-5-bromopyridine (10.1g), tetra-n-butylammonium chloride (13.1 g), palladium(II) acetate (0.08g) and sodium bicarbonate (9.87 g) in N,N-dimethylformamide (70 ml) wasstirred at 110pbC. for 6 hours. The reaction mixture was poured intoice-water and precipitated crystals were collected, washed with waterand dried to give 3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]nitrobenzene(12.0 g).

NMR (DMSO-d₆, δ): 2.11 (3H, s), 7.44 (1H, d, J=16Hz), 7.50 (1H, d,J=16Hz), 7.68 (1H, dd, J=8, 8Hz), 8.04 (1H, d, J=8Hz), 8.11 (3H, m),8.43 (1H, m or dd, J=1, 1Hz), 8.55 (1H, s, or d, J=1Hz).

PREPARATION 2

A mixture of 3-nitrostyrene (5.36 ml), 3,5-dibromopyridine (10.0 g),palladium(II) acetate (259 mg), tetra-n-butylammonium chloride (10.7 g)and sodium bicarbonate (8.07 g) in N,N-dimethylformamide (50 ml) wasstirred at 120pbC. for 4 hours. The mixture was poured into sodiumbicarbonate solution and extracted with ethyl acetate twice. Thecombined organic solution was washed with sodium bicarbonate solutionand brine, dried over magnesium sulfate and concentrated. The resultantsolid was washed with diisopropyl ether to give3-bromo-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (5.74 g).

NMR (CDCl₃, δ): 7.1-7.3 (2H, m), 7.59 (1H, t, J=8Hz), 7.82 (1H, d,J=8Hz), 8.02 (1H, t, J=2Hz), 8.18 (1H, dd, J=2, 8Hz), 8.39 (1H, t,J=2Hz), 8.11 (1H, d, J=2Hz), 8.67 (1H, d, J=2Hz).

PREPARATION 3

A mixture of 3,5-dibromopyridine (9.9 g),3-aminophenyl-dihydroxyboranepbhemisulfate (7.77 g),tetrakis(triphenylphosphine)palladium(0) (1.06 g) and 2M aqueous sodiumbicarbonate solution (42 ml) in toluene (85 ml) and methanol (21 ml) wasstirred at 80pbC. for 4.5 hours. The mixture was poured into sodiumbicarbonate solution and extracted with ethyl acetate twice. Thecombined organic solution was washed with sodium bicarbonate and brine,dried over magnesium sulfate and concentrated. The residue waschromatographed on silica gel column (4% methanol in chloroform) to give3-(3-aminophenyl)-5-bromopyridine (4.31 g).

NMR (DMSO-d₆, δ): 5.24 (2H, s), 6.64 (1H, m), 6.8-6.9 (2H, m), 7.14 (1H,t, J=8Hz), 8.19 (1H, t, J=2Hz), 8.66 (1H, d, J=2Hz), 8.78 (1H, d,J=2Hz).

PREPARATION 4

The following compound was obtained according to a similar manner tothat of Preparation 3.

(1) 3-(3-Acetamidophenyl)aniline

NMR (DMSO-d₆, δ): 2.05 (3H, s), 5.17 (2H, s), 6.54 (1H, m), 6.70 (1H,m), 6.80 (1H, m), 7.10 (1H, dd, J=8, 8Hz), 7.20 (1H, m), 7.32 (1H, dd,J=8, 8Hz), 7.50 (1H, m), 7.82 (1H, m)

MASS (m/z): 227 (M+1).

(2) 2-(3-Aminophenyl)-6-methoxynaphthalene

NMR (DMSO-d₆, δ): 3.89 (3H, s), 5.16 (2H, s), 6.56 (1H, m), 6.90 (1H,m), 6.96 (1H, m), 7.12 (1H, d, J=8Hz), 7.18 (1H, dd, J=8, 2Hz), 7.33(1H, m), 7.69 (1H, m), 7.88 (2H, m), 8.00 (1H, m).

PREPARATION 5

A mixture of 3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]nitrobenzene (3.0 g),iron powder (1.48 g) and ammonium chloride (0.57 g), ethanol (30 ml) andwater (9 ml) was stirred under reflux for 5 hours. The reaction wasfiltered, concentrated and extracted with chloroform. The extracts werechromatographed on silica gel (20 g, chloroform-methanol 100:1 aseluent) to give an oil. Crystallization from methanol afforded3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]aniline (2.4 g).

NMR (DMSO-d₆, δ): 2.10 (3H, s), 5.10 (2H, s), 6.50 (1H, m), 6.73 (2H,m), 7.05 (3H, m), 8.05 (2H, m), 8.48 (1H, m).

PREPARATION 6

A mixture of 3-bromo-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (5.55 g),iron powder (3.05 g) and ammonium formate (5.73 g) in ethanol (90 ml)and water (30 ml) was stirred at 90pbC. for 30 minutes. The mixture wasfiltered while hot. The filtrate was added to sodium bicarbonatesolution and extracted with ethyl acetate twice. The combined organicsolution was washed with sodium bicarbonate solution and brine, driedover magnesium sulfate and concentrated to give3-[(E)-2-(3-aminophenyl)vinyl]-5-bromopyridine (3.57 g).

NMR (DMSO-d₆, δ): 5.13 (2H, s), 6.54 (1H, d, J=8Hz), 6.79 (2H, m),7.0-7.1 (2H, m), 7.37 (1H, d, J=16Hz), 8.35 (1H, d, J=2Hz), 8.56 (1H, d,J=2Hz), 8.74 (1H, s).

PREPARATION 7

A mixture of 3-vinylaniline (8 g), 2-chloro-3-nitropyridine (10.7 g) andpotassium carbonate (18.6 g) in dioxane (80 ml) was stirred under refluxfor 5 days. The reaction was extracted with chloroform, washed withwater, dried over magnesium sulfate and evaporated. After evaporation ofthe solvent, crude residue was crystallized from methanol to give2-(3-vinylphenylamino)-3-nitropyridine as an orange crystals (12.9 g).

NMR (CDCl₃, δ): 5.30 (1H, d, J=12Hz), 5.79 (1H, d, J=16Hz), 6.75 (1H,dd, J=16, 12Hz), 6.85 (1H, dd, J=8, 4Hz), 7.25 (2H, m), 7.36 (1H, dd,J=8, 8Hz), 7.58 (1H, m), 7.67 (1H, s), 8.52 (2H, m).

PREPARATION 8

A mixture of 3-[(E)-2-(3-aminophenyl)vinyl]-5-bromopyridine (3.5 g),2-chloro-3-nitropyridine (2.22 g) and potassium carbonate (2.64 g) in1,4-dioxane (30 ml) was stirred under reflux for 22 hours. The mixturewas filtered and the filtrate was concentrated. The resultant solid waswashed with ethanol to give 2-[3-[(E)-2-(5-bromopyridin-3-yl)vinyl]phenylamino]-3-nitropyridine (1.63 g).

NMR (CDCl₃, δ): 6.89 (1H, dd, J=5, 8Hz), 7.03 (1H, d, J=16Hz), 7.20 (1H,d, J=16Hz), 7.3-7.5 (2H, m), 7.60 (1H, d, J=8Hz), 7.87 (1H, s), 8.00(1H, s), 8.5-8.6 (2H, m), 8.63 (1H, s).

PREPARATION 9

The following compounds were obtained according to a similar manner tothat of Preparation 7 or 8.

(1)2-[3-[(E)-2-(6-Acetamido-3-pyridyl)vinyl]phenylamino]-3-nitropyridine

NMR (DMSO-d₆, δ): 2.10 (3H, s), 7.00 (1H, dd, J=8, 5Hz), 7.22 (1H, d,J=16Hz), 7.30 (1H, d, J=16Hz), 7.39 (2H, m), 7.60 (1H, m), 7.84 (1H, m),8.06 (2H, m), 8.53 (3H, m).

(2) 2-[3-(5-Bromopyridin-3-yl)phenylamino]-3-nitropyridine

NMR (CDCl₃, δ): 6.90 (1H, dd, J=5, 8Hz), 7.38 (1H, d, J=8Hz), 7.52 (1H,t, J=8Hz), 7.69 (1H, d, J=8Hz), 7.98 (1H, m), 8.07 (1H, t, J=2Hz),8.5-8.6 (2H, m), 8.69 (1H, d, J=2Hz), 8.80 (1H, d, J=2Hz).

(3) 2-[3-(3-Acetamidophenyl)phenylamino]-3-nitropyridine

NMR (CDCl₃, δ): 2.20 (3H, s), 6.83 (1H, dd, J=8, 5Hz), 7.3-7.4 (4H, m),7.45 (1H, dd, J=8, 8Hz), 7.52 (1H, m), 7.67 (1H, m), 7.75 (1H, s), 7.83(1H, m), 8.52 (2H, m).

(4) 2-[3-(2-Methylbenzothiazol-6-yl)phenylamino]-3-nitropyridine

NMR (DMSO-d₆, δ): 2.80 (3H, s), 7.00 (1H, dd, J=8, 5Hz), 7.50 (2H, m),7.75 (2H, m), 7.96 (2H, m), 8.35 (1H, s), 8.55 (2H, m).

(5) 2-[3-(2-Methylbenzothiazol-5-yl)phenylamino]-3-nitropyridine

NMR (DMSO-d₆, δ): 2.81 (3H, s), 7.01 (1H, dd, J=8, 5Hz), 7.50 (2H, m),7.72 (2H, m), 8.02 (1H, s), 8.12 (1H, d, J=8Hz), 8.21 (1H, s), 8.53 (2H,m).

(6) 2-[3-(6-Methoxy-2-naphthyl)phenylamino]-3-nitropyridine

NMR (DMSO-d₆, δ): 3.90 (3H, s), 7.01 (1H, m), 7.20 (1H, m), 7.37 (1H,m), 7.50 (1H, dd, J=8, 8Hz), 7.57 (1H, m), 7.73 (1H, m), 7.84 (1H, m),7.93 (2H, m), 8.04 (1H, m), 8.18 (1H, s), 8.56 (2H, m).

PREPARATION 10

A mixture of 2-(3-vinylphenylamino)-3-nitropyridine (12.9 g),3-bromopyridine (12.7 g), palladium(II) acetate (0.24 g), copper(I)iodide (0.10 g), tri-o-tolylphosphine (0.65 g), triethylamine (25 ml)and acetonitrile (150 ml) was stirred under reflux under nitrogenovernight. After removal of the solvents, crude residue waschromatographed on silica gel (450 g, chloroform as eluent) to give2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]-3-nitropyridine as a reddishorange crystals (11.5 g).

NMR (DMSO-d₆, δ): 7.02 (1H, dd, J=8, 5Hz), 7.30 (1H, d, J=16Hz), 7.40(4H, m), 7.65 (1H, m), 7.88 (1H, m), 8.05 (1H, d, J=8Hz), 8.46 (1H, m),8.55 (2H, m), 8.80 (1H, m).

PREPARATION 11

The following compound was obtained according to a similar manner tothat of Preparation 10.

2-[3-[(E)-2-(5-Methoxycarbonylpyridin-3-yl)vinyl]phenylamino]-3-nitropyridine

NMR (DMSO-d₆, δ): 3.92 (3H, s), 7.02 (1H, dd, J=8, 5Hz), 7.42 (3H, m),7.56 (1H, d, J=16Hz), 7.68 (1H, m), 7.93 (1H, m), 8.55 (3H, m), 8.95(1H, br s), 9.05 (1H, br s).

PREPARATION 12

A mixture of2-[3-[(E)-2-(5-bromopyridin-3-yl)vinyl]phenylamino]-3-nitropyridine (800mg), 4-vinylpyridine (233 mg), palladium(II) acetate (27 mg),tetra-n-butylammonium chloride (616 mg) and sodium bicarbonate (432 mg)in N,N-dimethylformamide (4 ml) was stirred at 120pbC. for 4 hours. Themixture was poured into sodium bicarbonate solution and extracted withethyl acetate twice. The combined organic solution was washed withaqueous sodium bicarbonate and brine, dried over magnesium sulfate andconcentrated. The residue was crystallized from ethanol to give2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]-3-nitropyridine(346 mg).

NMR (CDCl₃, δ): 6.89 (1H, dd, J=5, 8Hz), 7.1-7.5 (8H, m), 7.62 (1H, d,J=8Hz), 7.87 (1H, s), 8.00 (1H, s), 8.5-8.7 (6H, m).

PREPARATION 13

The following compounds were obtained according to a similar manner tothat of Preparation 12.

(1)2-[3-[(E)-2-[5-[(E)-2-Methoxycarbonylvinyl]pyridin-3-yl]vinyl]phenylamino]-3-nitropyridine

NMR (CDCl₃, δ): 3.83 (3H, s), 6.59 (1H, d, J=16Hz), 6.89 (1H, dd, J=5,8Hz), 7.11 (1H, d, J=16Hz), 7.23 (1H, d, J=16Hz), 7.3-7.45 (2H, m), 7.61(1H, d, J=8Hz), 7.72 (1H, d, J=16Hz), 7.88 (1H, s), 7.96 (1H, t, J=2Hz),8.5-8.6 (2H, m), 8.62 (1H, d, J=2Hz), 8.73 (1H, d, J=2Hz).

(2)2-[3-[5-[(E)-2-(4-Pyridyl)vinyl]pyridin-3-yl]phenylamino]-3-nitropyridine

NMR (CDCl₃, δ): 6.90 (1H, dd, J=5, 8Hz), 7.15-7.6 (6H, m), 7.52 (1H, dt,J=8, 2Hz), 7.96 (1H, t, J=2Hz), 8.06 (1H, t, J=2Hz), 8.5-8.7 (4H, m),8.76 (1H, d, J=2Hz), 8.82 (1H, d, J=2Hz), 10.25 (1H, s).

PREPARATION 14

The mixture of 2-[3-(6-methoxy-2-naphthyl)phenylamino]-3-nitropyridine(5.2 g), N-bromosuccinimide (3.24 g) and benzoylperoxide (678 mg) inchloroform (30 ml) was refluxed for 3 hours. The mixture wasconcentrated in vacuo and was purified by column chromatography (silicagel) to obtain2-[3-(5-bromo-6-methoxy-2-naphthyl)phenylamino]-3-nitropyridine (3.3 g).

NMR (CDCl₃, δ): 4.05 (3H, s), 6.87 (1H, dd, J=8, 6Hz), 7.31 (1H, d,J=8Hz), 7.48-7.53 (2H, m), 7.65-7.73 (1H, m), 7.83-7.90 (2H, m), 7.95(1H, s), 8.00 (1H, s), 8.29 (1H, d, J=8Hz), 8.45-8.56 (2H, m).

PREPARATION 15

A solution of 2-[3-(3-acetamidophenyl)phenylamino]-3-nitropyridine (10g) in 3N hydrochloric acid (100 ml) was refluxed for 2 hours. The coldreaction was adjusted to pH 8 with saturated sodium bicarbonate solutionand precipitated reddish crystals were collected, washed with water anddried to give 2-[3-(3-aminophenyl)phenylamino]-3-nitropyridine (9.53 g).

NMR (DMSO-d₆, δ): 6.89 (1H, m), 7.01 (1H, dd, J=8, 5Hz), 7.17 (2H, m),7.30 (1H, m), 7.36 (1H, m), 7.45 (1H, dd, J=8, 8Hz), 7.68 (1H, m), 7.88(1H, m), 8.55 (2H, m).

PREPARATION 16

To an ice cooled suspension of 3-(2-pyridyl)acrylic acid (1.07 g) in drymethylene chloride (80 ml) was added triethylamine (1.46 g) and pivaloylchloride (0.87 g) and the mixture was stirred for 2 hours. After theclear reaction mixture was obtained,2-[3-(3-aminophenyl)phenylamino]-3-nitropyridine (2.0 g) was addedthereto and stirred under reflux overnight. The reaction waschromatographed on silica gel (chloroform-methanol 50:1 as an eluent) togive2-[3-[3-[(E)-3-(2-pyridyl)acryloylamino]phenyl]phenylamino]-3-nitropyridineas an orange crystal (2.85 g).

NMR (DMSO-d₆, δ): 7.02 (1H, dd, J=8, 5Hz), 7.35 (1H, d, J=16Hz), 7.42(4H, m), 7.50 (1H, m), 7.65 (2H, m), 7.71 (2H, m), 7.88 (1H, m), 7.94(1H, s), 8.08 (1H, s), 8.55 (2H, m), 8.66 (1H, m).

PREPARATION 17

The following compounds were obtained according to a similar manner tothat of Preparation 16.

(1)2-[3-[3-[(E)-3-(6-Acetamido-3-pyridyl)acryloylamino]phenyl]phenylamino]-3-nitropyridine

NMR (DMSO-d₆, δ): 2.11 (3H, s), 6.84 (1H, d, J=16Hz), 7.01 (1H, dd, J=8,5Hz), 7.35-7.50 (4H, m), 7.60 (1H, d, J=16Hz), 7.70 (2H, m), 7.91 (1H,m), 8.05 (2H, m), 8.18 (1H, m), 8.55 (3H, m).

(2)2-[3-[3-[(E)-3-(4-Pyridyl)acryloylamino]phenyl]phenylamino]-3-nitropyridin

NMR (DMSO-d₆, δ): 7.02 (1H, dd, J=8, 5Hz), 7.05 (1H, d, J=15Hz), 7.45(4H, m), 7.60 (3H, m), 7.72 (2H, m), 7.93 (1H, m), 8.05 (1H, m), 8.55(2H, m), 8.65 (2H, m).

PREPARATION 18

To a solution of3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (2.22 g) indichloromethane (70 ml) was added m-chloroperbenzoic acid (1.81 g). Themixture was stirred at room temperature for 1 hour, then poured intoaqueous sodium bicarbonate and extracted with chloroform. The organicsolution was washed with aqueous sodium bicarbonate and brine, driedover magnesium sulfate and concentrated. The residue was chromatographedon silica gel column (8% methanol in chloroform) to give3-nitro-2-[3-[(E)-2-(1-oxido-3-pyridyl)vinyl]phenylamino]pyridine (1.51g).

NMR (CDCl₃, δ): 6.85-7.0 (2H, m), 7.15-7.5 (5H, m), 7.62 (1H, d, J=8Hz),7.88 (1H, s), 8.12 (1H, d, J=5Hz), 8.38 (1H, s), 8.5-8.6 (2H, m).

PREPARATION 19

The following compounds were obtained according to a similar manner tothat of Preparation 18.

(1) 3-Nitro-2-[3-[(E)-2-(1-oxido-4-pyridyl)vinyl]phenylamino]pyridine

NMR (CDCl₃, δ): 6.89 (1H, dd, J=5, 8Hz), 7.01 (1H, d, J=16Hz), 7.20 (1H,d, J=16Hz), 7.3-7.5 (4H, m), 7.84 (1H, s), 8.19 (1H, d, J=7Hz), 8.5-8.6(2H, m).

(2)2-[3-[3-[(E)-3-(1-Oxido-4-pyridyl)acryloylamino]phenyl]phenylamino]-3-nitropyridine

NMR (DMSO-d₆, δ): 6.90 (1H, d, J=16Hz), 7.01 (1H, dd, J=8, 5Hz), 7.45(4H, m), 7.57 (1H, d, J=16Hz), 7.65 (2H, m), 7.70 (2H, m), 7.92 (1H, s),8.03 (1H, s), 8.25 (2H, m), 8.55 (2H, m).

PREPARATION 20

A mixture of2-[3-[(E)-2-(2-acetamido-3-pyridyl)vinyl]phenylamino]-3-aminopyridine(1.86 g), iron powder (1.39 g) and ammonium chloride (0.26 g), ethanol(20 ml) and water (6 ml) was stirred under reflux for an hour. Thereaction was filtered, concentrated and extracted with chloroform. Theextracts were washed with saturated sodium bicarbonate solution, driedand evaporated to afford2-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenylamino]-3-aminopyridine asdark purple crystals (1.59 g).

NMR (DMSO-d₆, δ): 2.10 (3H, s), 5.08 (2H, s), 6.64 (1H, dd, J=8, 5Hz),6.90 (1H, d, J=8Hz), 7.11 (2H, m), 7.23 (2H, m), 7.55 (2H, m), 7.77 (2H,m), 8.07 (2H, s), 8.50 (1H, s).

PREPARATION 21

A mixture of2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]-3-nitropyridine(331 mg), iron powder (132 mg) and ammonium formate (297 mg) in ethanol(6 ml) and water (2 ml) was stirred at 90pbC. for 30 minutes. Themixture was filtered while hot. The filtrate was added to aqueous sodiumbicarbonate solution and extracted with ethyl acetate twice. Thecombined organic solution was washed with sodium bicarbonate and brine,dried over magnesium sulfate and concentrated. The resultant solid waswashed with diisopropyl ether to give3-amino-2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]pyridine(270 mg).

NMR (DMSO-d₆, δ): 5.10 (2H, s), 6.67 (1H, dd, J=5, 8Hz), 6.92 (1H, d,J=8Hz), 7.1-7.3 (3H, m), 7.4-7.7 (7H, m), 7.81 (1H, s), 7.90 (1H, s),8.42 (1H, s), 8.61 (1H, d, J=5Hz), 8.69 (1H, s), 8.72 (1H, s).

PREPARATION 22

The following compounds were obtained according to a similar manner tothat of Preparation 20 or 21.

(1)2-[3-[3-[(E)-3-(2-Pyridyl)acryloylamino]phenyl]phenylamino]-3-aminopyridine

NMR (DMSO-d₆, δ): 6.75 (1H, m), 7.0-8.2 (15H, m), 8.65 (1H, m).

(2)2-[3-[3-[(E)-3-(6-Acetamido-3-pyridyl)acryloylamino]phenyl]phenylamino]-3-aminopyridine

NMR (DMSO-d₆, δ): 2.12 (3H, s), 5.10 (2H, br s), 6.65 (1H, m), 6.88 (2H,m), 7.11 (1H, m), 7.38 (3H, m), 7.60 (4H, m), 7.88 (1H, m), 8.04 (2H,m), 8.15 (1H, m), 8.55 (1H, m).

(3)3-Amino-2-[3-[(E)-2-[5-[(E)-2-methoxycarbonylvinyl]pyridin-3-yl]vinyl]phenylamino]pyridine

NMR (DMSO-d₆, δ): 3.77 (3H, s), 5.09 (2H, s), 6.65 (1H, dd, J=5, 8Hz),6.9-7.0 (2H, m), 7.1-7.3 (3H, m), 7.45-7.6 (3H, m), 7.7-7.9 (3H, m),8.52 (1H, s), 8.76 (2H, m).

(4)3-Amino-2-[3-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]phenylamino]pyridine

NMR (DMSO-d₆, δ): 5.11 (2H, s), 6.67 (1H, dd, J=5, 8Hz), 7.94 (1H, dd,J=2, 8Hz), 7.26 (1H, d, J=8Hz), 7.40 (1H, t, J=8Hz), 7.5-7.7 (5H, m),7.80 (1H, d, J=8Hz), 7.9-8.0 (2H, m), 8.32 (1H, s), 8.60 (1H, d, J=5Hz),8.78 (1H, d, J=2Hz), 8.82 (1H, d, J=2Hz).

(5) 3-Amino-2-[3-[(E)-2-(1-oxido-3-pyridyl)vinyl]phenylamino]pyridine

NMR (DMSO-d₆, δ): 5.10 (2H, s), 6.64 (1H, dd, J=5, 8Hz), 6.92 (1H, d,J=8Hz), 7.1-7.7 (8H, m), 7.81 (2H, m), 8.11 (1H, d, J=5Hz), 8.53 (1H,s).

(6) 3-Amino-2-[3-[(E)-2-(1-oxido-4-pyridyl)vinyl]phenylamino]pyridine

NMR (DMSO-d₆, δ): 5.10 (2H, s), 6.66 (1H, dd, J=5, 8Hz), 6.92 (1H, d,J=8Hz), 7.1-7.2 (2H, m), 7.28 (1H, t, J=8Hz), 7.37 (1H, d, J=16Hz),7.5-7.7 (4H, m), 7.8-7.9 (2H, m), 8.19 (1H, d, J=5Hz).

(7) 2-[3-(3-Acetamidophenyl)phenylamino]-3-aminopyridine

NMR (CDCl₃, δ): 2.13 (3H, s), 3.50 (2H, br s), 6.33 (1H, s), 6.77 (1H,dd, J=8, 5Hz), 7.00 (1H, d, J=8Hz), 7.12 (1H, dd, J=8, 2Hz), 7.2-7.4(5H, m), 7.50 (1H, m), 7.55 (1H, m), 7.61 (1H, s), 7.82 (1H, d, J=5Hz).

(8)2-[3-[3-[(E)-3-(1-Oxido-4-pyridyl)acryloylamino]phenyl]phenylamino]-3-aminopyridine

NMR (DMSO-d₆, δ): 5.10 (2H, s), 6.64 (1H, dd, J=8, 5Hz), 6.90 (1H, d,J=15Hz), 6.93 (1H, d, J=8Hz), 7.10 (1H, d, J=8Hz), 7.35 (2H, m), 7.45(1H, dd, J=8, 8Hz), 7.53 (1H, d, J=5Hz), 7.58 (1H, d, J=15Hz), 7.67 (4H,m), 7.90 (2H, d, J=8Hz), 8.00 (1H, m), 8.26 (2H, d, J=8Hz).

(9) 2-[3-(2-Methylbenzothiazol-5-yl)phenylamino]-3-aminopyridine

NMR (DMSO-d₆, δ): 2.80 (3H, s), 5.12 (2H, s), 6.64 (1H, m), 6.92 (1H,m), 7.20 (1H, m), 7.35 (1H, m), 7.52 (1H, m), 7.65 (1H, m), 7.71 (1H,m), 7.92 (1H, m), 8.00 (1H, m), 8.10 (2H, m).

(10) 2-[3-(2-Methylbenzothiazol-6-yl)phenylamino]-3-aminopyridine

NMR (DMSO-d₆, δ): 2.80 (3H, s), 5.15 (2H, s), 6.65 (1H, m), 6.95 (1H,m), 7.25 (1H, m), 7.35 (1H, m), 7.55 (1H, m), 7.75 (2H, m), 8.00 (3H,m), 8.30 (1H, m).

(11)2-[3-[(E)-2-(5-Methoxycarbonylpyridin-3-yl)vinyl]phenylamino]-3-aminopyridine

NMR (DMSO-d₆, δ): 3.92 (3H, s), 5.10 (2H, s), 6.65 (1H, dd, J=8, 5Hz),6.92 (1H, d, J=8Hz), 7.18 (1H, m), 7.28 (2H, m), 7.50 (1H, d, J=16Hz),7.54 (1H, m), 7.60 (1H, m), 7.80 (1H, s), 7.88 (1H, m), 8.50 (1H, m),8.94 (1H, s), 9.05 (1H, d, J=3Hz).

(12) 2-[3-(6-Methoxy-2-naphthyl)phenylamino]-3-aminopyridine

NMR (CDCl₃, δ): 3.45 (2H, br s), 3.93 (3H, s), 6.30 (1H, s), 6.80 (1H,dd, J=8, 5Hz), 7.04 (1H, m), 7.16 (2H, m), 7.30 (2H, m), 7.39 (1H, m),7.54 (1H, m), 7.71 (1H, m), 7.79 (2H, m), 7.87 (1H, m), 7.98 (1H, s).

(13) 2-[3-(5-Bromo-6-methoxy-2-naphthyl)phenylamino]-3-aminopyridine

NMR (CDCl₃, δ): 3.45 (1H, br s), 4.03 (3H, s), 6.34 (1H, br s), 6.79(1H, dd, J=6, 8Hz), 7.02 (1H, dd, J=8, 8Hz), 7.25-7.33 (4H, m),7.35-7.40 (1H, m), 7.57 (1H, m), 7.79-7.87 (3H, m), 7.95 (1H, s), 8.25(1H, m)

MASS (m/z): 420 (M+1), 422.

PREPARATION 23

The mixture of 2-[3-(6-methoxy-2-naphthyl)phenylamino]-3-aminopyridine(60 g) and pyruvic acid (18.6 g) in methanol was refluxed for 5 hours.The mixture was cooled and crystallized.2-Methyl-4-[3-(6-methoxy-2-naphthyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyridine(12.6 g) was collected by suction.

NMR (DMSO-d₆, δ): 2.51 (3H, s), 3.88 (3H, s), 7.20 (1H, m), 7.35 (2H,m), 7.40 (1H, dd, J=8, 5Hz), 7.66 (1H, dd, J=8, 8Hz), 7.81 (2H, m), 7.90(3H, m), 8.19 (1H, s), 8.23 (1H, m), 8.40 (1H, m).

PREPARATION 24

The following compound was obtained according to a similar manner tothat of Preparation 23.

4-[3-(3-Acetamidophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 190-193pbC.

NMR (CDCl₃, δ): 2.13 (3H, s), 4.32 (2H, s), 7.2-7.35 (5H, m), 7.45 (2H,m), 7.55 (1H, s), 7.62 (1H, dd, J=8, 8Hz), 7.70 (2H, m), 7.82 (1H, m),8.18 (1H, d, J=8Hz), 8.41 (1H, m), 8.49 (1H, d, J=5Hz), 8.73 (1H, s).

PREPARATION 25

The mixture of2-methyl-4-[3-(6-methoxy-2-naphthyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(3.4 g), N-bromosuccinimide (3.08 g) and benzoylperoxide (837 mg) inchloroform (30 ml) was refluxed for 3 hours. The mixture wasconcentrated in vacuo and was purified by column chromatography (silicagel) to obtain2-bromomethyl-4-[3-(6-methoxy-5-bromo-2-naphthyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(2.2 g).

NMR (CDCl₃, δ): 4.04 (3H, s), 4.71 (2H, s), 7.25-7.40 (3H, m), 7.65 (1H,m), 7.72 (1H, dd, J=8, 8Hz), 7.85 (3H, m), 8.02 (1H, s), 8.27 (2H, m),8.50 (1H, m)

MASS (m/z): 550 (M+1), 552, 554.

PREPARATION 26

The following compounds were obtained according to a similar manner tothat of Preparation 15.

4-[3-(3-Aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 202-204pbC.

NMR (CDCl₃, δ): 3.73 (2H, s), 4.32 (2H, s), 6.15 (1H, m), 6.90 (1H, m),6.98 (1H, d, J=8Hz), 7.25 (4H, m), 7.44 (1H, s), 7.62 (1H, dd, J=8,8Hz), 7.70 (1H, d, J=8Hz), 7.82 (1H, d, J=8Hz), 8.18 (1H, d, J=8Hz),8.43 (1H, d, J=5Hz), 8.50 (1H, m), 8.72 (1H, s).

EXAMPLE 1

A mixture of3-amino-2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]pyridine(260 mg) and 3-pyridylpyruvic acid (121 mg) in ethanol (5 ml) wasstirred under reflux for 5 hours. After removal of the solvent, theresidue was chromatographed on silica gel column (chloroform-methanol,9:1) and crystallized from methanol to give2-(3-pyridylmethyl)-3-oxo-4-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine(208 mg).

NMR (CDCl₃, δ): 4.33 (2H, s), 7.1-7.35 (7H, m), 7.40 (2H, d, J=5Hz),7.47 (1H, s), 7.55-7.7 (2H, m), 7.83 (1H, d, J=8Hz), 7.95 (1H, s), 8.20(1H, d, J=8Hz), 8.44 (1H, d, J=5Hz), 8.52 (1H, d, J=5Hz), 8.6-8.7 (4H,m), 8.74 (1H, s).

EXAMPLE 2

A suspension of2-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenylamino]-3-aminopyridine(1.5 g) and 3-pyridylpyruvic acid (0.79 g) in ethanol (30 ml) wasstirred under reflux for 8 hours. The cold reaction mixture was filteredand washed with ethanol to give2-(3-pyridylmethyl)-3-oxo-4-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenyl]-3,4-dihydropyrido[2,3-b]pyrazineas colorless crystals (1.76 g).

mp: 260-261pbC.

NMR (DMSO-d₆, δ): 2.10 (3H, s), 4.25 (2H, s), 7.27 (3H, m), 7.39 (2H,m), 7.58 (2H, m), 7.68 (1H, m), 7.78 (1H, m), 8.05 (2H, m), 8.22 (1H,m), 8.40 (1H, m), 8.45 (2H, m), 8.59 (1H, m)

EXAMPLE 3

The following compounds were obtained according to a similar manner tothat of Example 1 or 2.

(1)2-(3-Pyridylmethyl)-4-[3-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 253-257pbC.

NMR (CDCl₃, δ): 4.32 (2H, s), 7.13 (1H, d, J=16Hz), 7.2-7.4 (6H, m),7.53 (1H, m), 7.7-7.85 (3H, m), 8.03 (1H, t, J=2Hz), 8.21 (1H, dd, J=2,8Hz), 8.43 (1H, dd, J=2, 5Hz), 8.51 (1H, dd, J=2, 5Hz), 8.61 (2H, d,J=5Hz), 8.73 (2H, t, J=2Hz), 8.80 (1H, d, J=2Hz).

(2)4-[3-[3-[(E)-3-(2-Pyridyl)acryloylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 195-211pbC.

NMR (DMSO-d₆, δ): 4.27 (2H, s), 7.3-7.5 (8H, m), 7.6-7.8 (7H, m), 7.86(1H, dd, J=8, 8Hz), 8.05 (1H, m), 8.21 (1H, m), 8.40 (1H, m), 8.46 (1H,m), 8.60 (1H, m), 8.63 (1H, m).

(3)4-[3-[3-[(E)-3-(6-Acetamido-3-pyridyl)acryloylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 233-237pbC.

NMR (DMSO-d₆, δ): 2.11 (3H, s), 4.27 (2H, s), 6.80 (1H, d, J=16Hz), 7.40(5H, m), 7.57 (1H, d, J=16Hz), 7.68 (3H, m), 7.78 (2H, m), 8.04 (2H, m),8.19 (2H, m), 8.41 (1H, m), 8.45 (1H, m), 8.53 (1H, m), 8.60 (1H, m).

(4)2-(3-Pyridylmethyl)-4-[3-[(E)-2-[5-[(E)-2-methoxycarbonylvinyl]pyridin-3-yl]vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 196-199pbC.

NMR (CDCl₃, δ): 3.82 (3H, s), 4.31 (2H, s), 6.56 (1H, d, J=16Hz), 7.09(1H, d, J=16Hz), 7.2-7.35 (4H, m), 7.45 (1H, s), 7.55-7.75 (3H, m), 7.82(1H, dd, J=2, 8Hz), 7.90 (1H, d, J=2Hz), 8.20 (1H, dd, J=2, 8Hz), 8.44(1H, m), 8.51 (1H, m), 8.61 (1H, s), 8.69 (1H, s), 8.73 (1H, s).

(5)2-(3-Pyridylmethyl)-4-[3-[(E)-2-(1-oxido-3-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

NMR (CDCl₃, δ): 6.89 (1H, dd, J=5, 8Hz), 7.01 (1H, d, J=16Hz), 7.20 (1H,d, J=16Hz), 7.3-7.5 (4H, m), 7.84 (1H, s), 8.19 (1H, d, J=7Hz), 8.5-8.6(2H, m).

(6)2-(3-Pyridylmethyl)-4-[3-[(E)-2-(1-oxido-4-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

NMR (CDCl₃, δ): 4.32 (2H, s), 6.98 (1H, d, J=16Hz), 7.15-7.35 (6H, m),7.42 (1H, s), 7.55-7.7 (2H, m), 7.82 (1H, d, J=8Hz), 8.1-8.25 (3H, m),8.42 (1H, d, J=5Hz), 8.51 (1H, d, J=5Hz), 8.72 (1H, s).

(7)4-[3-[3-[(E)-3-(1-Oxido-4-pyridyl)acryloylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 190-195pbC.

NMR (DMSO-d₆, δ): 4.26 (2H, s), 6.87 (1H, d, J=16Hz), 7.3-7.5 (5H, m),7.55 (1H, d, J=16Hz), 7.6-7.8 (7H, m), 8.01 (1H, s), 8.22 (3H, m), 8.40(1H, d, J=5Hz), 8.47 (1H, d, J=5Hz), 8.60 (1H, s).

(8)4-[3-(2-Methylbenzothiazol-5-yl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 198-200pbC.

NMR (DMSO-d₆, δ): 2.80 (3H, s), 4.28 (2H, s), 7.37 (3H, m), 7.65-7.72(1H, m), 7.80 (2H, m), 7.91 (1H, m), 8.11 (1H, d, J=8Hz), 8.21 (2H, m),8.42 (1H, d, J=5Hz), 8.46 (1H, d, J=5Hz), 8.60 (1H, s).

(9)4-[3-(2-Methylbenzothiazol-6-yl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 241-243pbC.

NMR (DMSO-d₆, δ): 2.80 (3H, s), 4.27 (2H, s), 7.40 (3H, m), 7.65 (1H,dd, J=8, 8Hz), 7.80 (3H, m), 7.90 (1H, m), 7.97 (1H, d, J=8Hz), 8.22(1H, dd, J=8, 2Hz), 8.38 (1H, d, J=2Hz), 8.40 (1H, m), 8.45 (1H, m),8.60 (1H, d, J=2Hz).

(10)4-[3-[(E)-2-(5-Methoxycarbonylpyridin-3-yl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 171-173pbC.

NMR (DMSO-d₆, δ): 3.90 (3H, s), 4.26 (2H, s), 7.32 (1H, m), 7.40 (3H,m), 7.60 (2H, m), 7.68 (1H, s), 7.80 (2H, m), 8.22 (1H, d, J=8Hz), 8.42(1H, m), 8.48 (2H, m), 8.60 (1H, s), 8.95 (1H, m), 9.00 (1H, m).

(11)2-(3-Pyridylmethyl)-4-[3-(6-methoxy-5-bromo-2-naphthyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 211-214pbC.

NMR (CDCl₃, δ): 4.04 (3H, s), 4.34 (2H, s), 7.24-7.35 (4H, m), 7.60 (1H,m), 7.70 (1H, dd, J=8, 8Hz), 7.80-7.90 (4H, m), 8.00 (1H, m), 8.19 (1H,dd, J=8, 2Hz), 8.25 (1H, d, J=8Hz), 8.45 (1H, m), 8.50 (1H, m), 8.74(1H, m).

EXAMPLE 4

To a solution of2-(3-pyridylmethyl)-4-[3-[(E)-2-(3-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(374 mg) in dichloromethane (20 ml) was added m-chloroperbenzoic acid(232 mg). The mixture was stirred in ice bath for 1 hour, then pouredinto aqueous sodium bicarbonate and extracted with chloroform. Theorganic solution was washed with aqueous sodium bicarbonate and brine,dried over magnesium sulfate and concentrated. The residue waschromatographed on silica gel column (chloroform-methanol, 9:1) to give2-[(1-oxido-3-pyridyl)methyl]-4-[3-[(E)-2-(1-oxido-3-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(43 mg).

NMR (CDCl₃, δ): 4.29 (2H, s), 6.92 (1H, d, J=16Hz), 7.15-7.45 (8H, m),7.6-7.7 (2H, m), 8.13 (3H, m), 8.21 (1H, d, J=8Hz), 8.3-8.4 (2H, m),8.48 (1H, dd, J=2, 5Hz).

EXAMPLE 5

To a solution of4-[3-[(E)-2-(3,5-dichlorophenyl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(255 mg) in dichloromethane (10 ml) was added m-chloroperbenzoic acid(181 mg). The mixture was stirred at room temperature for 1 hour, thenpoured into aqueous sodium bicarbonate and extracted with chloroform.The organic solution was washed with aqueous sodium bicarbonate andbrine, dried over magnesium sulfate and concentrated. The resultantsolid was washed with diisopropyl ether to give4-[3-[(E)-2-(3,5-dichlorophenyl)vinyl]phenyl]-2-[(1-oxido-3-pyridyl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(167 mg).

NMR (CDCl₃, δ): 4.28 (2H, s), 6.97 (1H, d, J=16Hz), 7.1-7.45 (9H, m),7.55-7.7 (2H, m), 8.12 (1H, d, J=5Hz), 8.20 (1H, d, J=8Hz), 8.36 (1H,s), 8.47 (1H, m).

EXAMPLE 6

The following compounds were obtained according to a similar manner tothat of Example 4 or 5.

(1)4-[3-(3-Acetamidophenyl)phenyl]-2-[(1-oxido-3-pyridyl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

NMR (CDCl₃, δ): 2.16 (3H, s), 4.25 (2H, s), 7.24 (2H, m), 7.34 (3H, m),7.43 (2H, m), 7.52 (1H, m), 7.64 (1H, dd, J=8, 8Hz), 7.69 (1H, m), 7.73(2H, m), 8.12 (1H, m), 8.18 (1H, d, J=8Hz), 8.38 (1H, s), 8.45 (1H, d,J=5Hz)

(2)2-[(1-Oxido-3-pyridyl)methyl]-4-[3-[(E)-2-(1-oxido-4-pyridyl)vinyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 168-180pbC.

NMR (CDCl₃, δ): 4.28 (2H, s), 6.99 (1H, d, J=16Hz), 7.15-7.45 (8H, m),7.55-7.7 (2H, m), 8.1-8.25 (4H, m), 8.37 (1H, s), 8.47 (1H, m).

EXAMPLE 7

A solution of4-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(1.56 g) in 4N hydrochloric acid (30 ml) was refluxed for an hour. Thecold reaction was diluted with water and precipitated materials werecollected, washed with water and dried to give4-[3-[(E)-2-(6-amino-3-pyridyl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazinepbdihydrochloride(1.65 g).

mp: 215-222pbC.

NMR (DMSO-d₆, δ): 4.48 (2H, s), 7.08 (1H, d, J=8Hz), 7.20 (1H, d,J=16Hz), 7.28 (2H, m), 7.40 (1H, dd, J=8, 5Hz), 7.52 (1H, s), 7.58 (1H,dd, J=8, 8Hz), 7.66 (1H, d, J=8Hz), 8.02 (1H, dd, J=8, 5Hz), 8.06 (1H,s), 8.18 (1H, d, J=8Hz), 8.33 (3H, m), 8.42 (1H, d, J=5Hz), 8.52 (1H, d,J=8Hz), 8.83 (1H, d, J=5Hz), 8.92 (1H, s).

EXAMPLE 8

The following compound was obtained according to a similar manner tothat of Example 7.

4-[3-(3-Aminophenyl)phenyl]-2-[(1-oxido-3-pyridyl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

NMR (CDCl₃, δ): 4.27 (2H, s), 6.67 (1H, dd, J=8, 2Hz), 6.91 (1H, m),6.99 (1H, d, J=8Hz), 7.22 (3H, m), 7.31 (1H, dd, J=8, 5Hz), 7.43 (2H,m), 7.63 (1H, dd, J=8, 8Hz), 7.72 (1H, m), 8.13 (1H, m), 8.18 (1H, d,J=8Hz), 8.36 (1H, s), 8.45 (1H, d, J=5Hz).

EXAMPLE 9

To a suspension of4-[3-[(E)-2-(6-amino-3-pyridyl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazinepbdihydrochloride(0.3 g) was added triethylamine (0.17 g) andbis(trifluoroacetyl)anhydride (0.14 g). The resulted mixture was stirredfor additional 2 hours and precipitated colorless crystals werecollected, washed with methylene chloride and dried to give4-[3-[(E)-2-(6-trifluoroacetylamino-3-pyridyl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(0.28 g).

mp: 155-163pbC.

NMR (DMSO-d₆, δ): 4.40 (2H, s), 7.02 (1H, d, J=8Hz), 7.18 (1H, d,J=16Hz), 7.28 (2H, m), 7.41 (1H, dd, J=8, 5Hz), 7.53 (1H, s), 7.60 (1H,s), 7.68 (1H, m), 7.79 (1H, dd, J=8, 5Hz), 8.05 (1H, s) 8.20-8.35 (4H,m), 8.42 (1H, m), 8.71 (1H, m), 8.80 (1H, s).

EXAMPLE 10

To a solution of4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(300 mg) and triethylamine (0.33 ml) in 1,4-dioxane (10 ml) was added5-bromo-3-pyridylcarbonyl chloride·hydrochloride (304 mg). The mixturewas stirred at room temperature for 15 minutes, then poured into aqueoussodium bicarbonate and extracted with ethyl acetate. The organicsolution was washed with aqueous sodium bicarbonate and brine, driedover magnesium sulfate and concentrated. The residue was crystallizedfrom methanol to give4-[3-[(5-bromo-3-pyridyl)carbonylamino]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(256 mg).

mp: 223-226pbC.

NMR (CDCl₃, δ): 4.32 (2H, s), 6.78 (1H, d, J=8Hz), 7.12 (1H, dd, J=5,8Hz), 7.3-7.45 (2H, m), 7.56 (1H, s), 7.7-7.8 (2H, m), 8.2-8.3 (2H, m),8.32 (1H, m), 8.43 (1H, m), 8.65 (1H, s), 8.74 (1H, d, J=2Hz), 8.88 (1H,s), 8.91 (1H, s).

EXAMPLE 11

The following compounds were obtained according to a similar manner tothat of Example 10.

(1)4-[3-[3-[(E)-3-(4-Chlorophenyl)acryloylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 187-193pbC.

NMR (CDCl₃, δ): 4.33 (2H, s), 6.50 (1H, d, J=16Hz), 7.2-7.45 (8H, m),7.47 (1H, m), 7.52 (1H, m), 7.62 (2H, m), 7.72 (2H, m), 7.84 (3H, m),8.20 (1H, m), 8.42 (1H, m), 8.50 (1H, m), 8.75 (1H, s).

(2)4-[3-[3-[(E)-3-(3-Chlorophenyl)propenoylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 214-217pbC.

NMR (CDCl₃, δ): 4.33 (2H, s), 6.52 (1H, d, J=16Hz), 7.2-7.4 (8H, m),7.50 (2H, m), 7.54 (1H, m), 7.65 (3H, m), 7.74 (1H, m), 7.85 (2H, m),8.20 (1H, m), 8.43 (1H, m), 8.51 (1H, m), 8.75 (1H, m).

(3)4-[3-[3-[(E)-3-(2-Chlorophenyl)propenoylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 225-230pbC.

NMR (DMSO-d₆, δ): 4.27 (2H, s), 6.89 (1H, d, J=16Hz), 7.4 (8H, m), 7.55(1H, m), 7.67 (3H, m), 7.79 (3H, m), 7.88 (1H, d, J=16Hz), 8.07 (1H, m),8.20 (1H, m), 8.41 (1H, m), 8.46 (1H, m), 8.60 (1H, m).

(4)4-[3-[3-[(E)-3-(3-Pyridyl)acryloylamino]phenyl]-phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

mp: 185-191pbC.

NMR (DMSO-d₆, δ): 4.27 (2H, s), 7.03 (1H, d, J=16Hz), 7.40 (5H, m), 7.57(3H, m), 7.75 (5H, m), 8.01 (1H, s), 8.21 (1H, m), 8.41 (1H, m), 8.47(1H, m), 8.62 (3H, m).

(5)4-[3-[3-[(E)-3-(4-Pyridyl)acryloylamino]phenyl]phenyl]-2-[(1-oxido-3-pyridyl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine

NMR (CDCl₃, δ): 4.28 (2H, s), 7.05 (1H, d, J=16Hz), 7.2-7.5 (9H, m),7.62 (2H, m), 7.75 (2H, m), 7.95 (1H, m), 8.12 (1H, m), 8.19 (1H, m),8.43 (2H, m), 8.60 (2H, m), 9.25 (1H, m)

MASS (m/z): 553 (M+1).

EXAMPLE 12

To a stirred suspension of 2-(3-pyridyl)thiazole-4-carboxylic acid (0.56g) and triethylamine (0.55 g) in methylene chloride (25 ml) was addedpivaloyl chloride (0.33 g) in methylene chloride (5 ml) and the mixturewas stirred for 2 hours. After the reaction mixture was cleared,4-[3-(3-aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(1.0 g) was added thereto and the mixture was stirred under reflux for 2hours. The reaction mixture was washed with sodium bicarbonate solutionand water, dried over magnesium sulfate and concentrated. Crude residuewas chromatographed on silica gel (70 g, chloroform-methanol 100:1 aseluent) to give4-[3-[3-[2-(3-pyridyl)thiazol-4-ylcarbonylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazineas colorless crystals (0.48 g).

mp: 199-200pbC.

NMR (DMSO-d₆, δ): 4.28 (2H, s), 7.38 (3H, m), 7.50 (2H, m), 7.60 (1H,dd, J=8, 5Hz), 7.70 (2H, m), 7.80 (1H, m), 7.85 (1H, m), 7.95 (1H, m),8.20 (2H, m), 8.41 (1H, m), 8.48 (1H, m), 8.50 (1H, m), 8.58 (2H, m),8.73 (1H, m), 9.40 (1H, s).

EXAMPLE 13

The mixture of2-(bromomethyl)-4-[3-[2-(6-methoxy-5-bromo)naphthyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(4 g) and 1-acetylimidazole in N,N-dimethylformamide (40 ml) was stirredfor 5 hours at 70pbC. To the mixture was added saturated sodiumcarbonate (40 ml) and chloroform (40 ml). The mixture was stirred for 30minutes. The mixture was extracted by chloroform (2×40 ml). The organiclayer was evaporated in vacuo. The crude product was purified bychromatography to obtain2-(1-imidazolylmethyl)-4-[3-[(6-methoxy-5-bromo)-2-naphthyl]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine(1.7 g).

mp: 141-145pbC.

NMR (CDCl₃, δ): 4.03 (3H, s), 5.43 (2H, s), 7.12 (1H, m), 7.17 (1H, m),7.30 (2H, m), 7.35 (1H, dd, J=8, 5Hz), 7.61 (1H, m), 7.70 (1H, d,J=8Hz), 7.75 (1H, m), 7.85 (3H, m), 8.01 (1H, s), 8.21 (1H, d, J=8Hz),8.28 (1H, d, J=8Hz), 8.50 (1H, m)

MASS (m/z): 538 (M+1), 540.

What is claimed is:
 1. A compound of the formula: ##STR5## wherein R¹ ispyridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl orimidazolyl(lower)alkyl,R² is aminophenyl, [protected amino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl,[thiazolylcarbonylamino]phenyl which may have pyridyl on thiazolyl,naphthyl having lower alkoxy and halogen, [dihalophenyl](lower)alkenyl,[N-oxidopyridyl](lower)alkenyl, [aminopyridyl](lower)alkenyl, [protectedaminopyridyl](lower)alkenyl, [carboxypyridyl](lower)alkenyl, [protectedcarboxypyridyl](lower)alkenyl,[[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl,[[carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [[protectedcarboxy(lower)alkenyl]pyridyl](lower)alkenyl,[pyridyl(lower)alkenyl]pyridyl, lower alkylbenzothiazolyl or[halopyridylcarbonyl]amino,with proviso that when R² is[[4-pyridyl(lower)alkenoyl]amino]phenyl, aminophenyl, [loweralkanoylamino]phenyl or [dihalophenyl](lower)alkenyl, thenR¹ isN-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl, and apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,whereinR¹ is pridyl(lower)alkyl, N-oxidopyridyl(lower)alkyl orimidazolyl(lower)alkyl, R² is aminophenyl,[lower alkanoylamino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl,[[[acylaminopyridyl](lower)alkenoyl]amino]phenyl,[[pyridylthiazolyl]carbonylamino]phenyl, naphthyl having lower alkoxyand halogen, [dihalophenyl](lower)alkenyl,[N-oxidopyridyl](lower)alkenyl, [aminopyridyl](lower)alkenyl,[[acylamino]pyridyl](lower)alkenyl, [carboxypyridyl](lower)alkenyl,[esterified carboxypyridyl](lower)alkenyl,[[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl,[[carboxy(lower)alkenyl]pyridyl](lower)alkenyl, [[esterifiedcarboxy(lower)alkenyl]pyridyl](lower)alkenyl,[pyridyl(lower)alkenyl]pyridyl, lower alkylbenzothiazolyl orhalopyridylcarbonylamino,with the proviso that when R² is[[4-pyridyl(lower)alkenoyl]amino]phenyl, aminophenyl, [loweralkanoylamino]phenyl or [dihalophenyl](lower)alkenyl, then R¹ isN-oxidopyridyl(lower)alkyl or imidazolyl(lower)alkyl.
 3. The compound ofclaim 2, whereinR¹ is pyridyl(lower)alkyl, and R² is[[2-pyridyl(lower)alkenoyl]amino]phenyl,[[3-pyridyl(lower)alkenoyl]amino]phenyl,[[pyridylthiazolyl]carbonylamino]phenyl, [aminopyridyl](lower)alkenyl,[[lower alkanoylamino]pyridyl](lower)alkenyl,[[trihalo(lower)alkanoylaino]pyridyl](lower)alkenyl, [loweralkoxycarbonylpyridyl](lower)alkenyl,[[pyridyl(lower)alkenyl]pyridyl](lower)alkenyl or loweralkylbenzothiazolyl.
 4. The compound of claim 2, whereinR¹ isimidazolyl(lower)alkyl, and R² is naphthyl having lower alkoxy andhalogen.
 5. A process for preparing a compound of the formula: ##STR6##wherein R¹ and R² are each as defined in claim 1, or a salt thereof,which comprises(1) reacting a compound of the formula: ##STR7## whereinR² is as defined above, or a salt thereof with a compound of theformula: ##STR8## wherein R¹ is as defined above, or a salt thereof togive a compound of the formula: ##STR9## wherein R¹ and R² are each asdefined above, or a salt thereof, or (2) subjecting a compound of theformula: ##STR10## wherein R¹ is as defined above, and R_(a) ² is[aminopyridyl](lower)alkenyl, or its reactive derivative at the aminogroup, or a salt thereof to acylation reaction to give a compound of theformula: ##STR11## wherein R¹ is as defined above and R_(b) ² is[acylaminopyridyl](lower)alkenyl, or a salt thereof, or (3) subjecting acompound of the formula: ##STR12## wherein R¹ is as defined above,R_(c)² is [lower alkanoylamino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl,[thiazolylcarbonylamino]phenyl which may have pyridyl or[acylaminopyridyl](lower)alkenyl, or a salt thereof to deacylation togive a compound of the formula: ##STR13## wherein R¹ is as definedabove, and R_(d) ² is aminophenyl or [aminopyridyl](lower)alkenyl, or asalt thereof, or (4) reacting a compound of the formula: ##STR14##wherein R¹ is as defined above, andR_(e) ² is aminophenyl, or itsreactive derivative at the amino group, or a salt thereof with acompound of the formula:

    R.sup.3 --OH

wherein R³ is lower alkanoyl, [halophenyl](lower)alkenoyl,pyridyl(lower)alkenoyl, [N-oxidopyridyl](lower)alkenoyl, [protectedaminopyridyl](lower)alkenoyl or thiazolylcarbonyl which may havepyridyl, or its reactive derivative at the carboxy group, or a saltthereof to give a compound of the formula: ##STR15## wherein R¹ is asdefined above, and R_(f) ² is [lower alkanoylamino]phenyl,[[[halophenyl](lower)alkenoyl]amino]phenyl,[[pyridyl(lower)alkenoyl]amino]phenyl,[[[N-oxidopyridyl](lower)alkenoyl]amino]phenyl, [[[protectedaminopyridyl](lower)alkenoyl]amino]phenyl or[thiazolylcarbonylamino]phenyl which may have pyridyl, or a saltthereof, (5) subjecting a compound of the formula: ##STR16## wherein R²is as defined above,R⁵ is N-protective group, A is lower alkylene, andY⁻ is halide, or a salt thereof to elimination of N-protective group togive a compound of the formula: ##STR17## wherein R² and A are each asdefined above, or a salt thereof.
 6. A pharmaceutical composition whichcomprises, as an active ingredient, a compound of claim 1 or apharmaceutically acceptable salt thereof in admixture withpharmaceutically acceptable carriers.
 7. A method for the prophylacticor therapeutic treatment of phosphodiesterase IV (PDE-IV) and tumornecrosis factor (TNF) mediated diseases which comprises administering acompound of claim 1 or a pharmaceutically acceptable salts thereof tohuman or animals.
 8. A process for preparing a pharmaceuticalcomposition which comprises admixing a compound of claim 1 or apharmaceutically acceptable salt thereof with a pharmaceuticallyacceptable carrier.
 9. The compound of claim 2,wherein[[[acylaminopyridyl](lower)alkenoyl]amino]phenyl is [[[[loweralkanoylamino]pyridyl](lower)alkenoyl]amino]phenyl);[[acylamino]pyridyl](lower)alkenyl is [[loweralkanoylamino]pyridyl](lower)alkenyl or [[mono (or di or tri)halo(lower)alkanoylamino]pyridyl](lower)alkenyl; [esterifiedcarboxypyridyl](lower)alkenyl is [loweralkoxycarbonylpyridyl](lower)alkenyl; and [[esterifiedcarboxy(lower)alkenyl]pyridyl](lower)alkenyl is [[loweralkoxycarbonyl(lower)alkenyl]pyridyl](lower)alkenyl.